Process for the preparation of imidazolones



UNITED STATES PATENT OFFICE PROCESS FOR THE PREPARATION OF IMIDAZOLON ES Robert Duschinsky, Essex Fells, N. J., assignor to Hoffmann-La Roche Inc., Nutley, N. J., a. corporation of New Jersey N Drawing. Application March 21, 1946, Serial No. 656,146

7 Claims. (Cl. 260-309) This invention relates to a novel method for at 50-55". After cooling it was neutralized to the decarboxylation of compounds of the general pH '7 by gradual addition of 37.5 cc. N HCl, which formula: was accompanied by much carbon dioxide evolu- 00 tion and crystallization of the reaction product. 5 The mixture was stirred in an ice bath for 1 hour, the methylimidazolone filtered ofi and washed X.C=C.COOY chlorine free with some ice cold water. After (A) drying in an oven at 60, a first crop of 6.6 g. i. was obtained. M. P. 184492". obtam products of the genel a1 formula" The mother-liquor was concentrated in vacuo, Q while the pH, which had the tendency to increase, HN NH was adjusted to 7 by gradual addition of 7 cc. N Realm HCl, and was finally brought to dryness. The (3) white residue was extracted 3 times with 35 cc. of

v boiling absolute ethanol, and once with 95 per- Whel em X and Y lepresent alkyl such as cent ethanol. The alcoholic extracts, after sepapropyl and the ration from the undissolved sodium chloride, were The mventlon also relates to the novel concentrated to dryness, thus yielding a second pounq 4'me1.;hy1.imid.aZO1one 2! crop of 8.55 g. methylimidazolone melting at ca.

This application is a continuation-impart of Total yield: 1515 application Serial No. 533,396, filed April 29, 1944, sometime th s e first crop of reaction product Patent 2397250 granted Malqh did not crystallize directly, but only after partial Reference also made to my copendmg apphca' concentration of the solution in vacuo. tion Serial No. 590,509, filed April 26, 1945, now To obtain a pure Same the Substance was twice abandonedrecrystallized from 2 volumes boiling water M P I have fOund that if wmpwnds of the general 2025-2045 (after softening at 190). For the formula (A) given above are saponified, de analysis it was sublimed at 1 mm. (200 bath). boxylamon takes place to produce compounds of The substance is soluble in water, methanol,

the general formula This decarboxylation ethanol acetone also in hot dioxane ethylaceis quite Surprising in its action inasmuch as it tate and nitrobenzene' insoluble in benzene would be expected that saponification of comchloroform ether and ptroleum ether. pounds of the gfeneral formula (A) would result The aqueous or alcoholic solution reduces n the production only of the corresponding ammoniacal silver nitrate and gives with ferric imidazolone-carboxyhc acids. The reaction apchlorde oluti n a dee ur le coloration. pears to involve an imtial formation of a labile 1 s 0 pp p carboxylic acid, followed by decarboxylation with- 0 EXAMPLE 2 out intermediate isolation of that acid.

After the saponification, the reaction mixture *emglzmzdazolonea is neutralized, and the alkylimidazolone is sepa- To a Solution of 16.8 ethyl propionylacetate rated- The decarboxylatior} can effected by 0 (prepared according to Breslow, Baumgarten and means of an aqueous alkaline solution, such as Hauser A1I1 Chem soc 56, 1286, (1944) in 27 Sodlum hydroxlde banum hydroxlde m the cc. acetic acid, there was added dropwise with Presence of heatstirring and within 1 hour a solution of 7.36 g. The Products produced accordmg to my process sodium nitrite in 18 cc. water, the temperature are useful as intermediates in the preparation of being kept by cooling at 5 to 0 G Then 60 F Organic compounds such as biotin, desthio water were added and stirring was continued, mount and analogs thereofwhile the temperature was allowed to rise to 26 Examples of carrymg my trfmsformatlon C. within 2 hours. After eliminating some exare glven for the purpose of lnustmtlon: cess of nitrous acid by addition of 4 g, urea, the MPL 1 5o mixture was extracted twice with cc. ether.

The ether extract was washed 3 times with 15 cc. 4'methyhmzdazolone'z sodium bicarbonate solution, the third washing 34 g. 4-methyl-5-imidazolone-(2)-carboxylic being alkaline. After drying the ethereal soluacid ethyl ester were dissolved in 215 cc. 0.93 N tion over sodiumsulfate, the solvent was evap- NaOH (1 mole) and the solution kept 68 hours orated, leaving 13.53 g. of a light yellow oil,

d"26=1.439. This product was ethyl-a-oximinopropionyl acetate.

A mixture of 3.05 g. foregoing oximino-compound, 13.5 cc. ethanol, 1.76 cc. 10 N hydrochloric acid and 35 cc. water, was hydrogenated for 40 minutes in the presence of 0.6 g. palladium charcoal catalyst containing 3.3 percent palladium at about 1600 pounds p. s. 1. pressure and at a temperature of 30-33 C. After filtering from the catalyst, 1.76 cc. N hydrochloric acid, and a solution of 2.14 g. potassium cyanate in 9 cc. water were added. The mixture was concentrated on a water bath in an evaporating dish until the volume was 20 cc. Upon cooling 1.94 g. 4-ethyl-5- imidazolone-(2) -carboxylic acid ethyl ester crystallized, which melted at 171-173". Recrystallization from water and sublimation at 0.6 mm. and

200 (bath) raised the melting point to 182-184 C. For the following decarboxylation step the crude product was used.

To a solution of 3.94 g. 4-ethyl ester in 214 cc. boiling water was added a solution of 9 g. crystallized barium hydroxide octohydrate in 50 cc. boiling water. After heating the mixture for 4 /2 hours at 85 C. the deposited barium carbonate, amounting to 4.3 g., was filtered off. The small amount of barium still remaining was eliminated as sulfate by addition of 11.2 cc. N sulfuric acid to the solution. The latter was concentrated to dryness, the residue was recrystallized from 20 cc. water. Yield: 1.45 g. melting at 192-194. Evaporation of the mother liquor yielded a second crop of 0.37 g. The isolated 4-ethylimidazolone-2 gives an intense purple ferric chloride reaction. It can be sublime'd at 0.7 mm. and 170-175 C. (bath). Kolshorn (Ber. 37, 2477, (1904) obtained ethylimidazolone from aminomethyl ethyl ketone, but reported a considerably lower melting point, namely, 166-167.

EXAMPLE 3 4-methyZimida2ol0ne-2 To a solution of 340 g. (2 moles) of 4-methyl-5- imidazolone-(Z) -carboxylic acid ethyl ester in 1450 c. of water and 840 cc. of ethanol, which was kept refluxing with continuous stirring, a hot solution of 680 g. (2.15 moles) of crystallized barium hydroxide in 2800 cc. of water, was added gradually within two hours. Too fast addition of the barium hydroxide results in a bulky precipitate which disintegrates with difficulty. Heating and stirring was then continued for four to six hours, until the precipitation of the heavy, fast-settling barium carbonate was complete. After filtering the hot solution, the small residual amount of barium was eliminated by addition of ca. 250 cc. of N sulfuric acid. Evaporation gave a crystallizing sirup which was dissolved in cc. of boiling water and cooled. A bulky crystalline, slightly yellowish mass resulted, which was sucked dry and washed with a little ice-cold water. Yield -150 g. M. P. -188". The product was 4-methy1imidazolone-2.

Wherever the term imidazolone or its structural formula is shown, all tautomeric forms are intended to be embraced.

I claim:

1. A process which comprises decarboxylating by saponifying compounds of the general formula:

to produce compounds of the general formula:

X. :(BH wherein X and Y represent lower alkyl.

2. The process of claim 1 in which X represents methyl.

3. The process of claim ethyl.

4. The process of claim 1 in saponifying agent is employed.

5. The process of claim 1 in which the reaction is carried out by means of an aqueous alkaline solution at a temperature of about 50-60.

6. The process of claim 1 in which barium hydroxide solution is employed as the saponifying agent.

7. The process of claim 1 in which the saponification is carried out by means of an aqueous alkaline solutionfollowed by neutralization of the solution and isolation of the resulting 4-alkylimidazolone-2.

1 in which X represents which an alkaline ROBERT DUSCHINSKY.

REFERENCES CITED Berichte, vol. 26, (1893) page 2204. Beilstein, 4th edition, vol. 24, page 62. 

